1 Phenylalkylamines (PAA) usually known for their action on L-type Ca 2+ channels potently block the C-type inactivating lymphocyte Kv1.3 channel resulting in inhibition of activation of T lymphocytes. In order to design PAAs blocking Kv1.3 speci®cally over L-type Ca 2+ channels, we investigated the state-dependent manner of mKv1.3 block by the PAA verapamil. 2 Verapamil seems to have access to the open state (OB) and, once bound to the channel, the channel-verapamil complex is absorbed into a slowly recovering state. This state was proposed to be the inactivated blocked state (IB). Here we present a quantitative description of the transition into this state and provide evidence for the IB state through experiments with an inactivation lacking mutant channel. Since the inactivated state cannot be reached in this case the IB state cannot be reached either. 3 We show that the transition OB?IB is accelerated by verapamil most likely through a mechanism involving the reduction of [K + ] at an inactivation modulating low anity binding site for K + at the outer vestibule. 4 Measurements of the voltage-dependence of the o-rate constants for verapamil suggest that verapamil can reach the channel in its neutral form and might get partially protonated while bound. Thus only those verapamil molecules that are protonated can more easily dissociate at hyperpolarizing voltages. 5 Since open block kinetics were shown to be similar for wild type mKv1.3 and the H404T mutant mKv1.3 channel, and since the block of the H404T mutant channels by verapamil could be described exactly by a simple three-state open block model, the mutant channel could serve as a screening channel to determine open block anities of new PAA derivatives in high through-put experiments.